Family History and Spinophilin Genotype Influence on NMDA Receptor Function and Ethanol Response In the CTNA Overview, we hypothesize that disturbances in the interplay of glutamate and dopamine systems contribute to the vulnerability to alcohol dependence by: 1) impairing the normal engagement of reward/motivation circuitry and thereby increasing the relative motivational impact of alcohol-related rewards;and 2) by shifting the reward valence of the N-methyl-D aspartate (NMDA) glutamate receptor antagonist component of ethanol action toward reward, making ethanol a more addictive substance for those at risk. Project 3 will explore the latter hypothesis by evaluating whether increases in NMDA receptor function associated with a family history of alcohol dependence are associated with changes in the "reward valence" of ethanol. In this study, NMDA receptor function, assessed by evaluating the response to the NMDA receptor antagonist ketamine, and ethanol response, assessed using the ethanol "clamp" procedure (to minimize the impact of pharmacokinetic variability), will be determined. By exploring the relationship between ketamine and ethanol response, we can examine the extent to which NMDA receptor antagonism contributes to the balance of the positive (stimulant, euphoric) and negative (sedative, dysphoric) effects of ethanol, i.e. its reward valence. A family history of alcoholism is a risk factor for the development of alcohol dependence. A component of the familial risk for alcoholism appears to be expressed as a change in the reward valence to ethanol effects. This study will test the hypothesis that both ketamine and alcohol response will be similarly influenced by family history of alcoholism within subjects. If so, it would suggest that heritable factors influencing NMDA receptor function contribute to one of the most important biomarkers for the heritable risk for alcohol dependence. Further, this study will begin to explore the impact of variation in genes that contribute to alterations in NMDA receptor function associated with the familial vulnerability to alcohol dependence.